Dopaminergic and angiotensin regulation of sodium metabolism via the sodium bicarbonate co-transporter (SLC4A5) in the human renal proximal and distal tubule cells: Role of GRK4 on salt sensitivity

项目1摘要 这项研究计划的目的是扩展我们的研究，如何肾素血管紧张素系统， (RAS)多巴胺能系统调节肾钠转运， 参与盐敏感性的病因学（影响51%的高血压和高血压的病理学）， 26%的正常血压个体）。具体来说，我们将测试总体假设， 产电碳酸氢钠协同转运蛋白NBCe 2（由基因SLC 4A 5编码）和 NBCe 1（由SLC 4A 4基因编码）通过调节参与钠稳态 通过RAS和多巴胺能系统和其他关键的钠转运蛋白（NHE 3和 Na+，K+/ATP酶）。此外，SLC 4A 5中的两个单核苷酸多态性（SNP）导致了 钠重吸收通过增加SLC 4A 5 mRNA表达而失调， NBCe 2活性。本项目的具体目的是：（1）验证盐 敏感性是由于肾近端小管的异常多巴胺能和血管紧张素调节所致 由SLC 4A 5中的内含子变体和GRK 4的变体（GRK 4 - 65 L）引起的钠转运， (2)为了检验具体目标1中的假设，通过研究表观遗传调控， 通过SLC 4A 5中的HNF 4A结合位点表达NBCe 2（和相关离子转运蛋白） 基因

ABSTRACT FOR PROJECT 1 The goal of this research proposal is to extend our studies of how the renin angiotensin system (RAS) and dopaminergic systems regulate renal sodium transport and ultimately their involvement in the etiology of salt sensitivity (a pathology affecting 51% of hypertensive and 26% of normotensive individuals). Specifically, we will test the overall hypothesis that the electrogenic sodium bicarbonate cotransporters NBCe2 (coded by the gene SLC4A5) and NBCe1 (coded by the gene SLC4A4) are involved with sodium homeostasis through regulation by the RAS and dopaminergic systems and other critical sodium transporters (NHE3 and Na+,K+/ATPase). Furthermore, two single nucleotide polymorphisms (SNPs) in SLC4A5 lead to the dysregulation of sodium reabsorption through increases in SLC4A5 mRNA expression and NBCe2 activity. The specific aims for this project are: (1) To test the hypothesis that salt sensitivity is due to aberrant dopaminergic and angiotensin regulation of renal proximal tubule sodium transport caused by intronic variants in SLC4A5 and a variant of GRK4 (GRK4-65L) and (2) To test the hypothesis in specific aim 1 by investigating the epigenetic regulation of the expression of NBCe2 (and related ion transporters) by an HNF4A binding site in the SLC4A5 gene.